L1: Principles of Vet Toxicology (Martyniuk)

Question 1

dosimetry

Answer 1

the idea that “all substances are poisons and there is none which is not a poison. The right dose differentiates poison from remedy.” (idea of Paracelsus)

Question 2

Diclofenac

Answer 2

an anti-inflammatory used in cattle

-vultures feed on cattle treated with Diclofenac –> kidney failure

Question 3

how many manmade chemicals are potential toxins?

Answer 3

> 50,000

Question 4

how many toxic plants?

Answer 4

> 800

Question 5

toxic vs. toxicology vs. toxicant

Answer 5

toxic: poisonous
toxicology: science of poisons (concerned w/ ID, tx, and assessing risks of poisons)
toxicant: compound that causes toxicity (natural or man-made)

Question 6

xenobiotic

Answer 6

foreign substance found within an organism

Question 7

4 main factors influencing toxicity

Answer 7

1) Toxicant: structure, metabolism, elimination, size, charge (chem/biological properties)
2) Exposure: (dose, time exposed, route of exposure, conc.)
3) Subject: breed, age, health, species
4) Environment: temp, bioavailability, altitude, etc.

Question 8

3 classifications of chemical interactions in toxicity

Answer 8

additive
antagonistic
synergism

Question 9

dose-response relationship

Answer 9

central concept of toxicology; assumes a cause and effect relationship and that response is proportional to dose. Shape of curve is always sigmoidal

Question 10

NOAEL

Answer 10

No observable adverse effect level: max. dose that causes no adverse effect

Question 11

LOAEL

Answer 11

Lowest Observable Adverse Effect Level: min. dose that you can measure an effect.

Question 12

LD50:

Answer 12

dose producing death in 50% of animals

Question 13

Threshold dose:

Answer 13

min. dose to produce reaction; indicates there is “safe” dose

Question 14

acute exposure

Answer 14

single dose exposure or several doses w/n 24hr

Question 15

sub-acute/subchronic exposure

Answer 15

exposure over 7-90d

Question 16

chronic exposure

Answer 16

protracted exposure (6mo-lifetime)

Question 17

toxicokinetics

Answer 17

study of the movement and disposition of the toxicant in an organism (ADME)

• influenced by dose, physiochemical properties of the toxin/drug, species differences in physiological and biochemical chars.
• math. rep. of how a toxin gets into, moves about, and causes an effect on the body

Question 18

Does exposure = dose?

Answer 18

NO

Question 19

ADME

Answer 19

absorption, distribution, metabolism, excretion

Question 20

major routes of excretion:

Answer 20

renal (urine), hepatic (bile), fecal, GIT

Question 21

absorption

Answer 21

uptake of material from site of exposure; the amt. of material that enters the body

Question 22

distribution

Answer 22

from blood to tissues

Question 23

metabolism

Answer 23

enzymatic conversion
aka biotransformation: the biological conversion of a chemical compound (exogenous or endogenous) into a second compound, or metabolite
-requires enzyme catalysts (phase I or II)
-primary biochemical pathway of xenobiotic metabolism

Question 24

elimination

Answer 24

excretion from body. Can follow first or zero order kinetics

-influenced by half-life (when 50% of the compound is degraded)

Question 25

3 main routes of exposure

Answer 25

1) Lungs (pulmonary surfaces)
- uptake of vapors, gases, mists, particulates
2) Gut (dietary exp.)**
- influenced by pH of gut, rate of digestion, residence time of food, microflora of gut
3) Dermis**
- hydrophobic compounds can go through skin of animals

Question 26

Order 6 common absorption routes from fastest to slowest:

Answer 26

IV
Pulmonary
IM
IP
Oral
Cutaneous

Question 27

which is absorbed faster: aspirin or pesticide?

Answer 27

aspirin

Question 28

things that can affect drug distr.

Answer 28

solubility, protein binding, physical characteristics/health of animal, pH, charge of compound, transporters/receptors for a certain compound, etc.

Question 29

what happens between applied dose and target organ dose?

Answer 29

applied dose –> absorption –> internal dose –> distribution –> target organ dose

Question 30

central medium of distr. of chemical that target organs

Answer 30

blood

Question 31

main sites of biotransformation reactions

Answer 31

liver and kidney

• have highest enzyme conc.
• blood flow
• high surface area

Question 32

phase I enzymes

Answer 32

increase hydrophilicity of compounds by adding reacting groups such as hydroxyl, thiol, carboxyl via REDOX reactions

Question 33

phase II enzymes

Answer 33

increase hydrophilicity of compounds even further by forming inactive conjugates with addition of acetate, glucoronic acid, glycine, glutathione, etc. Use PRIMARY CONJUGATION reactions.

• have more species differences than phase I enzymes
• bigger proteins than Phase I

Question 34

Biotransformation can lead to:

Answer 34

• enhanced elimination (lipophylic to hydrophylic)
• detoxification
• sequestration
• redistribution
• activation

Question 35

possible adverse effects of sequestration

Answer 35

body still holding onto the toxin. If sequestration pathway randomly stops working, you can get serious acute adverse effect.

Question 36

bioactivation

Answer 36

making compound more toxic by metabolizing it
Ex: parathion (pesticide) –> oxidation –> paraoxon
*parathion is especially toxic to pregnant animals

Question 37

cats deficient in which metabolism process?

Answer 37

glucuronidation

Question 38

dogs deficient in which metabolism process?

Answer 38

acetylation

Question 39

guinea pigs/rats deficient in which metabolism process?

Answer 39

N-hydroxylation

Question 40

pigs deficient in which metabolism process?

Answer 40

sulfation

Question 41

name 3 ex. of compounds that bioactivate

Answer 41

benzopyrene
aflatoxin (a fungus)
acetaminophen

Question 42

acetaminophen metabolism

Answer 42

acetaminophen activated by cytochrome P450 (a phase I enzyme) to N-acetyl-p-Benzoquinoneimine, which causes oxidative stress in tissues and ROS formation.

Question 43

name 3 P450 inhibitors

Answer 43

cimetidine
enrofloxacin
grapefruit juice

Question 44

name a P450 inducer

Answer 44

ethanol

Question 45

2013 top 10 toxins

Answer 45

1) prescription pharmaceuticals
2) insecticides
3) OTC drugs (NSAIDs)
4) household products
5) human foods
6) vet meds (i.e. ivermectin)
7) chocolate
8) rodenticides (i.e. Warfarin)
9) toxic plants
10) lawn products

Question 46

First-order elimination

Answer 46

constant FRACTION of chemical eliminated (dose dependent). plasma drug concentration decreases linearly with time.
-most common form of elimination

Question 47

Zero-order elimination

Answer 47

constant AMOUNT of chemical eliminated; typically means that processes are saturated.

• dose INDEPENDENT
• acetaminophen, alcohol

Question 48

most pesticides have short/long half-lives

Answer 48

short. (ie. Fipronel). Usually present with acute exposure.

Question 49

How do toxicants cause toxicity?

Answer 49

1) Cellular damage, resulting from free radical damage, inhibiton of energy production, disruption of enzyme function
- i.e. Acetaminophen, arsenic
2) Organ system dysfunction (not assoc. with specific cellular injury, but lethal to intact organism)
- i.e. Insecticides, rodenticides